Search

Background Meningiomas are the most common tumors occurring in the central nervous system, with variable recurrence rates depending on World Health Organization grading. Atypical (Grade II) meningioma has a higher rate of recurrence than benign (Grade I) meningioma. The efficacy of adjuvant radiotherapy (RT) to improve tumor control has been questioned. Objective To investigate clinical and histopathological predictors of tumor recurrence and radio-resistance in atypical meningiomas. Methods This cohort study retrospectively reviewed all patients in St. Michael's Hospital CNS tumor patient database who underwent surgical resection of a Grade II meningioma from 1995 to 2015. Cases with neurofibromatosis type II, multiple satellite tumors, spinal cord meningioma, radiation-induced meningioma, and perioperative death were excluded. Patient demographics, neuropathological diagnosis, tumor location, extent of resection, radiation therapy, and time to recurrence or progression were recorded. Cox univariate regression and Kaplan-Meier survival analysis were employed to identify risk factors for recurrence and radio-resistance. Results Among 181 patients, the combination of necrosis and brain invasion was associated with an increased recurrence risk (hazard ratio [HR] = 4.560, P = .001) and the lowest progression-free survival (PFS) relative to other pathological predictors. This trend was maintained after gross total resection (GTR, P = .001). RT was associated with decreased PFS (P = .001), even in patients who received GTR (P = .001). Conclusion The combination of necrosis and brain invasion is a strong predictor of tumor recurrence and radio-resistance in meningioma, regardless of EOR or adjuvant RT. Our findings question the sensibility of brain invasion as an absolute criterion for Grade II status.

BACKGROUND The relationship between sleep, neuropathology, and clinical manifestations of Alzheimer's disease (AD) remains controversial. OBJECTIVE To determine whether nighttime behaviors (NTB) are associated with the development of AD histopathology or cognitive decline. METHODS We compared NTB prevalence in subjects with or without AD lesions, and with or without progressive cognitive decline. Subjects with either absent or severe plaques and tangles were identified from the National Alzheimer's Disease Coordinating Center data sets and classified as cognitively declining if the standard deviation from their individual mean Mini-Mental Status Examination score was ≥2, and stable if

INTRODUCTION: Spinal hemangiomas are benign vascular tumors that most commonly originate from the osseous structures of the spinal column. Epidural spinal hemangiomas without osseous involvement are uncommon and are classified as pure epidural spinal hemangiomas. Extraosseous spinal epidural cavernous hemangiomas are rarely described and among available reports; most patients present with slowly progressive neurological symptoms. Herein, we present a novel case of acute neurological dysfunction from a pure spinal epidural hemangioma that was managed through surgical resection with good neurological recovery at follow-up. CASE PRESENTATION: A 45-year-old previously healthy man presented to the emergency room with sudden inability to ambulate and was found to have bilateral lower extremity weakness. Magnetic resonance imaging of the spine demonstrated an epidural mass extending out of the right T5/6 neural foramen. The mass enhanced heterogeneously, and the preoperative diagnosis favored an atypical schwannoma. The lesion was surgically removed en-bloc through a midline posterior decompression with instrumentation. Histopathologic examination confirmed cavernous hemangioma pathology. Within 6 weeks of the surgical intervention, the patient had regained full sensorimotor function and these effects were durable through long term follow-up. DISCUSSION: Pure spinal epidural hemangiomas are rare and generally have an insidious clinical course. This case report highlights that these uncommon lesions may present with substantial and acute neurological dysfunction requiring urgent neurosurgical intervention. This should prompt clinicians to consider cavernous hemangioma in the differential diagnosis of patients presenting with acute neurological deterioration and an epidural spinal tumor.

Introduction Neuropsychiatric symptoms (NPS) are both common in mild cognitive impairment and Alzheimer disease (AD). Studies have shown that some NPS such as apathy and depression are a key indicator for progression to AD. Methods We compared Neuropsychiatric Inventory (NPI) total score and NPI subdomain score between mild cognitive impairment-converters (MCI-C) and mild cognitive impairment-nonconverters (MCI-NC) longitudinally for 6 years using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In addition to the NPI, Mini-Mental State Examination (MMSE) scores were also compared to find out if MMSE scores would differ between different NPI groups. Lastly, a linear regression model was done on MMSE and NPI total score to establish a relationship between MMSE and NPI total score. Results The results in this study showed that NPI total scores between MCI-C and MCI-NC differed significantly throughout 6 years. MCI-C subjects had a higher mean NPI total score and lower MMSE score compared with MCI-NC subjects. In addition, MMSE scores were significantly different between the 3 groups of NPI total score. Subjects who have a high NPI score have the lowest mean MMSE score, thus demonstrating that NPI scores do indeed affect MMSE scores. Further analyses using a regression model revealed that a unit change in NPI total score lead to 0.1 to 0.3 decrease in MMSE. Discussion On the basis of the findings, this study showed evidence that increase in NPS burden (reflected by increase in NPI) over time predicts conversion to AD, whereas stability of symptoms (reflected by stable NPI score) favors nonconversion. Further study should investigate the underlying mechanisms that drive both NPS burden and cognitive decline.

BACKGROUND: Delusions affect approximately a third of Alzheimer’s disease(AD) patients and are associated with poor outcomes. Previous studies investigating the neuroanatomical correlates of delusions have yet to reach a consensus, with findings of reduced volume across all the lobes, particularly in frontal regions. The current study examined the grey matter(GM) differences associated with delusions in AD. METHODS: Using voxel-based morphometry(VBM), we assessed GM for 23 AD patients who developed delusions(AD+D) and 36 comparable AD patients who did not develop delusions(AD-D) at baseline and follow up. ANOVA was used to identify consistent differences between AD+D and AD-D patients across both timepoints(main effect of group), consistent changes from baseline to follow up(main effect of time) and differential changes between AD+D and AD-D over time(interaction of group and time). All data were obtained from the NACC database. RESULTS: The AD+D group had consistently lower frontal GM volume, although both groups showed decreased GM in fronto-temporal brain regions over time. An interaction was observed between delusions and longitudinal change, with AD+D patients having significantly elevated GM in predominantly temporal areas at baseline assessment, which had declined to become significantly lower than the AD-D group at follow-up. CONCLUSION: These findings suggest that although individuals with and without delusion show long-term GM decreases, there are specific volumetric markers that distinguish patients with delusion from those without, before and after the onset of delusions. Specifically, the decline of GM in temporal areas that were elevated prior to the onset of delusion may be involved in the manifestation of delusions.

Neuropsychiatric symptoms (NPS) are common sequelae of traumatic brain injuries (TBI) among adults. However, little is known about NPS associated with a history of TBI in adults relative to adults without a history of TBI and to what extent NPS may be modulated by sex and other factors. Using the National Alzheimer's Coordinating Center Uniform Data Set, we examined the association between Neuropsychiatric Inventory-Questionnaire (NPI-Q) scores in cognitively normal older adults with and without a history of TBI. A binomial logistic regression model was used to examine NPI-Q domains in adults with a history of TBI (n = 266) versus without a history of TBI (n = 1508). History of TBI, sex, age, and body mass index were used as covariates. Adults with a history of TBI had a greater probability of exhibiting agitation, anxiety, apathy, disinhibition and aberrant motor behavior relative to adults without a history of TBI. In terms of sex differences, males with and without a history of TBI had an increased likelihood of agitation, apathy, disinhibition, and apnea, whereas females had an increased likelihood of anxiety and insomnia relative to males. Our study confirms that history of TBI is associated with an increased prevalence of specific NPS, including agitation, anxiety, apathy, disinhibition, and aberrant motor behavior. Given that the aforementioned NPS are linked through different pathways, damage to any of them may cause an alteration in behavior. As well, NPS appear to be modulated by sex, with symptoms differing between males and females. Our research suggests future studies examining NPS sequelae of TBI should adjust for sex.

Purpose To validate ferumoxytol-based quantitative blood oxygenation level-dependent (BOLD) MRI for mapping oxygenation of human infiltrative astrocytomas by using intraoperative measurement of tissue oxygen tension and histologic staining. Materials and Methods Fifteen patients with infiltrative astrocytomas were recruited into this prospective multicenter study between July 2014 and December 2016. Prior to treatment, participants underwent preoperative quantitative BOLD MRI with ferumoxytol to generate tissue oxygen saturation (StO2) maps. Two intratumoral sites were identified, one with low StO2 and one with high StO2. Neuronavigation was used to locate sites intraoperatively for insertion of oxygen-sensing probes to measure local tissue oxygen tension (PtO2). Biopsies from both sites were taken and stained for markers of hypoxia (hypoxia-inducible factor 1α, carbonic anhydrase IX) and neoangiogenesis (vascular endothelial growth factor, endoglin [CD105]). Spearman correlation and nonparametric sign-rank tests were used to analyze data. Results Ten patients with median age of 58.5 years (interquartile range, 25 years; four men and six women) completed the study. Because there is no linear relationship between StO2 and PtO2, the ratios of low to high StO2 versus low to high PtO2 in each patient were compared and a significant correlation was found (r = 0.73; P = .01). Pathologic analyses revealed differences between carbonic anhydrase IX (P = .03) for sites of low StO2 versus high StO2. CD105 displayed a similar trend but was not significant (P = .09). Conclusion Ferumoxytol-based quantitative blood oxygenation level-dependent MRI can potentially be used as a noninvasive surrogate for oxygenation mapping in infiltrative astrocytomas. This technique can potentially be integrated in treatment planning for aggressive targeting of hypoxic areas in tumors.

Introduction The relative contributions of vascular and degenerative pathology to dementia are unknown. We aim to quantify the proportion of dementia explained by potentially preventable vascular lesions. Methods We systematically searched for population-based cohorts before February 2017 reporting clinicopathological data for individuals with and without dementia. We calculated the summary proportion and absolute risk of dementia comparing subjects with and without the pathology. Results We identified 10 studies comprising 2856 subjects. Vascular-type pathology and mixed pathology are respectively two and three times more likely in demented patients. The summary proportion of dementia is 77%–86% in subjects with mixed degenerative and vascular pathology and 45% in subjects with pure Alzheimer-type pathology. Discussion Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component.

Congenital cytomegalovirus (CMV) infection in the 2supnd/supand 3suprd/suptrimester results in catastrophic CNS abnormalities. This susceptibility is thought to result from the high proportion of neural stem cells in the developing brain. In immunocompromised adults, CNS infection by CMV preferentially affects ependymal surfaces, from where it expands to involve the parenchyma. Experimental models of murine CMV infection demonstrate viral tropism for the dentate gyrus (DG) and subventricular zone, the areas in which adult neurogenesis occurs. We present two cases of CMV infection of the DG of immunocompromised allogeneic stem cell transplant recipients. Both cases showed CMV-positive neurons in the DG granular cell layer, as well as contiguous layers. The majority of infected cells contained Nissl substance and expressed nestin, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), and neurofilament. These cases demonstrate that CMV infects the DG in humans. Co-expression of nestin and GFAP, indicative of early neurogenesis, is consistent with experimental models showing neural stem cells as the target of CMV, providing further histological evidence of neurogenesis in the human dentate. Finally, the cases suggest that CMV infection produces abnormal migration of newly formed neurons as evidenced by the finding of virally infected neurons in the molecular layer of the dentate. .

Background Molecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a DNA-methylation-based classifier into clinical practice and report its impact on CNS tumor patient diagnosis and treatment. Methods Prospective case review was undertaken at CNS tumor board discussions over a 3-year period and 55 tumors with a diagnosis that was not certain to two senior neuropathologists were recommended for methylation profiling based on diagnostic needs. Tumor classification, calibrated scores, and copy number variant (CNV) plots were obtained for all 55 cases. These results were integrated with histopathological findings to reach a final diagnosis. We retrospectively reviewed each patient's clinical course to determine final neuro-pathology diagnoses and the impact of methylation profiling on their clinical management, with a focus on changes that were made to treatment decisions. Results Following methylation profiling, 46 of the 55 (84%) challenging cases received a clinically relevant diagnostic alteration, with two-thirds having a change in the histopathological diagnosis and the other one-third obtaining clinically important molecular diagnostic or subtyping alterations. WHO grading changed by 27% with two-thirds receiving a higher grade. Patient care was directly changed in 15% of all cases with major changes in clinical decision-making being made for these patients to avoid unnecessary or insufficient treatment. Conclusions The integration of methylation-based CNS tumor classification into diagnostics has a substantial clinical benefit for patients with challenging CNS tumors while also avoiding unnecessary health care costs. The clinical impact shown here may prompt the expanded use of DNA methylation profiling for CNS tumor diagnostics within prominent neuro-oncology centers globally.

INTRODUCTION: Older adults are particularly vulnerable to poor long term outcomes and the rate of TBI in this group is increasing. Studies have shown females experience worse outcome from TBI than males, however this research has been limited. The aim of this study is to examine gender effects on the frequency of sleep disturbances in older adults post TBI. METHODS: An analysis was conducted on data obtained from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set. A total of 405 patients greater than 60 years of age were examined. Sleep disturbances were measured using the Nighttime Behavioural Disturbances domain of theNeuropsychiatric Inventory – Questionnaire (NPI-Q) RESULTS: A significant difference (p=0.025) in reported sleep disturbance was identified in the female TBI population relative to the female non-TBI population. In the male No TBI group, 14.8% (n=12) experienced nighttime disturbances while those with TBI experienced 19.8% (n=17). This difference was not significant (p=0.305). CONCLUSION: These results suggest there is a greater impact from traumatic brain injury on sleep disturbances in older females than males. Further research examining gender differences in older adults related to neuropsychiatric outcomes of TBI should be considered given the implications for treatment.

We report two different cases of IgG4-related hypophysitis. In the first case, a pituitary lesion was accompanied by lymphocytic meningitis possibly mimicking tuberculous meningitis. The second case was unassociated with involvement of other organs. No histologic differences were noted between the two cases indicating that the morphologic features of the hypophysial lesion do not depend on the presence of other lesions. The pathogenesis of IgG4 hypophysitis is not known, and further study is necessary to explore the cause, progression, and influencing factors of this disease.

BACKGROUND Neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD. OBJECTIVE To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(-)] of agitation/aggression (A) in autopsy-confirmed AD. METHODS Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control group or corrections for multiple comparisons. RESULTS 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p = 0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits. CONCLUSIONS Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions.

Background: The pathophysiology behind psychosis in patients with Alzheimer’s disease (AD) remains unknown. Recently, vascular risk factors have been recognized as important modifiers of the clinical presentation of AD. Objective: The purpose of our study is to investigate the mechanism through which vascular risk factors mediate psychosis and whether or not it involves cerebrovascular lesions. Methods: Data was provided by the National Alzheimer’s Coordinating Centre. The Uniform Data Set was used to collect information on subject-reported history of vascular risk factors, clinician-reported state of cognitive performance, and presence of psychosis based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). The Neuropathology Data Set was used to evaluate the presence of vascular lesions and the severity of AD pathology. Subjects with high probability of AD based on the NIA/AA Reagan criteria were included in the analysis. Results: We identified 1,459 patients with high probability of AD and corresponding NPI-Q scores. We confirmed the association between hypertension and diabetes on psychosis, specifically in delusions and the co-occurrence of delusions and hallucinations. Furthermore, the presence of white matter rarefaction based on pathological evaluation was associated with hallucinations. A history of vascular risk factors was positively associated with vascular lesions. However, vascular lesions in the presence of vascular risk factors did not increase the likelihood of psychosis. Furthermore, vascular lesions were not associated with greater cognitive or functional impairments in this group with severe AD pathology. Conclusion: Vascular risk factors and vascular lesions are independently associated with psychosis in patients with severe AD. However, vascular lesions are not the mechanism through which vascular risk factors mediate psychosis.

Ganglioglioma (GG) is a mixed glio-neuronal tumour, comprised of a neoplastic glial component and dysplastic ganglion cells. GG is a tumour of unclear histogenesis; previous studies examining BRAF mutations and chromosome imprinting has provided evidence that both the neuronal and glial components likely arise from a common precursor. Both p.V600E mutation and KIAA1549-BRAF fusion have been described in pilocytic astrocytoma (PA) and GG, but they differ with regards to the rates of different BRAF alterations, and careful histological examination is an important component of patho-molecular correlations. More recently, cases of PA with gangliocytic differentiation (PA-GD) have been described, and these cases are thus far restricted to those with the KIAA1549-BRAF fusion. Here, we describe three cases of GGs in patients with history of previously diagnosed PAs. The cases differ with respect to the chronologic intervals between the PA and the GG diagnoses. In two of the cases, where the PA-GG diagnostic intervals are less than ten years, pathological review revealed the older specimens to have been misdiagnosed as PAs. In the third case, where the interval spanned multiple decades, the GG was found to be positive for both BRAF p.V600E immunohistochemistry (IHC) and for the KIAA1549-BRAF fusion. Molecular study for the BRAF p.V600E mutation was negative, proving the IHC result to be a false-positive. Our case demonstrates that cases of GG can harbour the KIAA1549-BRAF fusion, even with positive BRAF p.V600E IHC results, and the case highlights a diagnostic challenge that may be encountered.

BACKGROUND Aberrant motor behavior (AMB) is a neuropsychiatric symptom (NPS) prevalent in Alzheimer's disease (AD), known to cause great distress to both patients and caregivers. Apolipoprotein E4 (APOE4) is the most important genetic predictor of AD, and it has been associated with high NPS prevalence. OBJECTIVE To investigate the neuropathological substrates and risk factors associated with AMB in AD patients. METHODS Cases with Braak stage I-II and CERAD 0-1 were classified as Low AD (LAD), while Braak stage III-IV and CERAD 2 were grouped as Intermediate AD (IAD). Cases with Braak stage V-VI and CERAD 3 were classified as High AD (HAD) in accordance with NIA-Reagan criteria. All cases were stratified by APOE genotype, yielding No ɛ4 & ɛ4 and ɛ4/ɛ4 groups depending on ɛ4 copy number within APOE. Presence of AMB was assessed using NPI-Q. RESULTS AND CONCLUSION AMB increased in parallel with CERAD and Braak & Braak scores. Hypercholesterolemia, but no other cardiovascular risk factors, was associated with AMB in HAD. AMB prevalence in HAD was significantly increased in the presence of two APOEɛ4 alleles as compared to No ɛ4 & ɛ4. The relationship between homozygous APOE4 and AMB was strongly associated with the presence of both Lewy bodies and cerebral amyloid angiopathy pathologies in both sexes.

Background: The Apolipoprotein (APOE) ε4 allele is a well-known risk factor for Alzheimer’s Disease (AD), and sleep disturbances are commonly associated with AD. However, few studies have investigated the relationship between APOE ε4 and abnormal sleep patterns (N+) in AD. Objective: To examine the relationship between APOE genotype, Lewy body pathology, and abnormal sleep patterns in a large group of subjects with known AD load evaluated upon autopsy. Method: Data from 2,368 cases obtained from the National Alzheimer’s Coordinating Centre database were categorized as follows: Braak Stage V/VI and CERAD frequent neuritic plaques as high load AD, Braak Stage III/IV and moderate CERAD as intermediate load AD, and Braak Stage 0/I/II and infrequent CERAD as no to low load AD. Cases discrepant between the two measures were discarded. Results: Disrupted sleep was more frequent in males (42.4%) compared to females (35.1%), and in carriers (42.3%) as opposed to non-carriers (36.5%) of ε4. Amongst female subjects with high AD load and Lewy body pathology, homozygous (ε4/ε4) carriers experienced disrupted sleep more often compared with heterozygous (ε4/x) or non-carriers of ε4. Such recessive, gender-specific, and Lewy body association is reminiscent of the ε4 effect on psychosis in AD. However, such association was lost after adjusting for covariates. In subjects with no to low AD pathology, female ε4 carriers had significantly more nighttime disturbances than non-carriers; this effect is independent of the presence of Lewy body pathology. Conclusion: The influence of APOE ε4 on sleep disturbances is dependent on gender and severity of AD load.

Background: The neuropathological correlates of psychosis in Alzheimer’s disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association. Objective: To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD. Method: We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to the NPI-Q, were analyzed separately. Results: 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis. Method: Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.

Primary or metastatic melanocytic tumors in the sellar region are rare and can pose a diagnostic challenge. Here we describe a case of a 74-year-old man who underwent radiological investigations for a transient episode of blurred vision. Based on the clinical and endocrinological findings and MRI results, the patient was assumed to have a clinically non-functioning pituitary macroadenoma, which was followed-up over a 2-year period. He did not have any endocrine symptoms or progressive visual deterioration, and no history of past malignancy, including melanoma. Endocrinological investigation was unremarkable; blood hormone levels were within the normal ranges except for low serum total testosterone and bioavailable testosterone levels without symptoms of hypogonadism. The longitudinal MRI follow-up demonstrated a gradual increase in the size of the tumor over the course of 11 months. For this reason, the patient underwent surgery. Pathologic examination including histology, immunohistochemistry and electron microscopy achieved the correct diagnosis of melanocytic tumor of the sellar region morphologic examination is essential in the diagnosis of melanocytic tumors. Hmb-45 is an important diagnostic biomarker in melanocytic lesions. The use and exploration of miRNA, Ki67 and osteopontin are important in understanding the genesis, progression, and prognosis in treatment of patients with melanocytic tumors.

INTRODUCTION Despite having severe Alzheimer disease pathology, some individuals remain cognitively asymptomatic (cASYM). To explore noncognitive manifestations in these cASYM individuals, we aim to investigate the prevalence and pathologic substrates of psychosis. METHODS Data were obtained from the National Alzheimer's Coordinating Center. The Neuropsychiatric Inventory Questionnaire, quick version was used to evaluate presence of psychosis. Subjects with Mini-Mental Status Examination score of ≥24 with frequent neuritic plaques (NPs) were defined as NPcASYM, and those with Braak and Braak stage of neurofibrillary tangles of V/VI were defined as NTcASYM (both groups collectively designated cASYM). Logistic regression analysis was used to examine the association between NP and neurofibrillary tangle severity and psychosis accounting for potential confounders. RESULTS We identified 667 subjects with Mini-Mental Status Examination score of ≥24, of which 137 were NPcASYM and 96 were NTcASYM. NPcASYM were at significantly higher risk of having psychosis compared with those with moderate or sparse/no NP (odds ratio, 2.47; 95% confidence interval, 1.54-3.96). NTcASYM were also at higher risk compared with those with Braak and Braak stage I to IV, but the association explained by the effect of Lewy body pathology and microinfarcts. DISCUSSION The load of NP may be an important substrate of psychosis in individuals who show no gross cognitive symptoms.

Objective The incidence of giant cell arteritis (GCA) is insufficiently documented for Canada, but important to ascertain for public health planning. We estimate the incidence of biopsy-proven GCA (BPGCA) in Kingston, Ontario, and for the province of Ontario. Method The number of cases of BPGCA was tabulated from retrospective chart review of all temporal artery biopsies (TABx) in Kingston, Ontario from 2011–15. The relevant population denominator was determined from the Canada census federal electoral district and the patient’s postal code. The province-wide estimate for the incidence of BPGCA was calculated from provincial billing data of TABx from 2015–17, the Canada census for Ontario, and the expected positive yield of TABx. Results There were 35 subjects with BPGCA in the Kingston area over the 4-year period, from a population of 179 503 individuals 50 years of age or older (≥50 years). Ontario billing data identified 2404 patients who underwent TABx for suspected GCA over a 2-year period, from a population of 5 143 610 persons ≥50 years. Meta-analysis of 5 provincial TABx series suggested a 21% positive yield from TABx procedures (95% CI 0.18–0.24). The minimum cumulative incidence of BPGCA was 4.9 per 100 000 persons ≥50 years in Kingston, and 4.9 (95% CI 4.2–5.6) per 100 000 persons ≥50 years for Ontario as a whole. Conclusion The estimated incidence of BPGCA in Ontario using 2 different estimation techniques was comparable, but low compared with other countries. The actual incidence of GCA in Ontario may be higher.

International audience; Immunohistochemical (IHC) α-synuclein (Asyn) pathology in peripheral biopsies may be a biomarker of Parkinson disease (PD). The multi-center Systemic Synuclein Sampling Study (S4) is evaluating IHC Asyn pathology within skin, colon and submandibular gland biopsies from 60 PD and 20 control subjects. Asyn pathology is being evaluated by a blinded panel of specially trained neuropathologists. Preliminary work assessed 2 candidate immunoperoxidase methods using a set of PD and control autopsy-derived sections from formalin-fixed, paraffin-embedded blocks of the 3 tissues. Both methods had 100% specificity; one, utilizing the 5C12 monoclonal antibody, was more sensitive in skin (67% vs 33%), and was chosen for further use in S4. Four trainee neuropathologists were trained to perform S4 histopathology readings; in subsequent testing, their scoring was compared to that of the trainer neuropathologist on both glass slides and digital images. Specificity and sensitivity were both close to 100% with all readers in all tissue types on both glass slides and digital images except for skin, where sensitivity averaged 75% with digital images and 83.5% with glass slides. Semiquantitative (0-3) density score agreement between trainees and trainer averaged 67% for glass slides and 62% for digital images.

Recent reports have characterized functional lymphatic vessels, which drain both fluid and immune cells from the CSF to the deep cervical lymph nodes, lining the dural sinuses in mice. If conserved in the human brain these vessels could have profound implications for neuroinflammatory and neurodegenerative diseases. We provide evidence of the presence of lymphatic vessels in human dura obtained at autopsy, at the level of the superior sagittal sinus, in 4 individuals. Immunohistochemistry for the lymphatic vessel endothelial cell marker podoplanin revealed the widespread presence of multiple structures with a distinct lumen distributed throughout the superior sagittal sinus. These vessels provide a putative infrastructure for drainage of macromolecules from the brain parenchyma and represent an exciting avenue of exploration for involvement in the pathogenesis of neurodegenerative proteinopathies including Parkinson's disease.

Background Symptoms of psychosis is one of the common clinical manifestations of Alzheimer's disease (AD). However, the pathophysiology behind psychosis is unknown. Objective The aim of the present study was to explore the relationship between Apolipoprotein E (APOE) genotype, Lewy body pathology, and psychosis in AD. Method The data was obtained from the National Alzheimer's disease Coordinating Centre (NACC), using the Uniform Data Set and the Neuropathology Data Set. Subjects with frequent neuritic plaque on CERAD, and Braak Stage of V or VI, corresponding to high probability of AD based on the NIA-AA Regan criteria were included in the analysis. Results Subjects with two copies of e4 alleles were significantly more likely to develop psychosis, both delusions and/or hallucinations, during the course of their illness. This association was gender-specific, only reaching significance in females. Our findings further showed that presence of two copies of e4 allele was positively associated with the formation of Lewy bodies. Only in females with Lewy bodies was the effect of two copies of e4 allele significant, reaching an odd ratio of 4.5. Conclusion The APOE e4 allele has a female-specific effect in inducing psychosis in AD through the formation of Lewy bodies.

Intracranial hemangioblastomas are benign vascular tumors. The peak age of incidence is between 20 to 50 years. Hemangioblastomas rarely occur in patients over the age of 65. To our knowledge there is no review of the prevalence and clinical features in an elderly population. We reviewed our 12 year experience with intracranial hemangioblastomas, and characterized the clinical features of hemangioblastomas in patients over the age of 65. We present a 72-year-old man with a cerebellar mass initially thought to be a metastasis as an illustrative case. We reviewed our pathology database and identified all patients with a histopathologically confirmed diagnosis of hemangioblastoma over the last 12 years in a large tertiary adult hospital; all patients were over the age of 18. Of all cases of hemangioblastoma in the last 12 years, six of 77 (7.7%) occurred in patients over the age of 65. All were cerebellar in location, and none were associated with von-Hippel Lindau disease. Hemangioblastomas are uncommon, but not rare, in patients over the age of 65, and should be included in the differential diagnosis of patients presenting with gait ataxia and a cerebellar lesion in this age group.

Hemangioblastomas are benign tumors, derived from "stromal" cells of unclear origin. While previously thought to be a rare entity in elderly patients, we had previously reported a case series of six elderly patients (aged over 65years at diagnosis) diagnosed with hemangioblastoma in our 12year experience. Here, we report a followup series, describing eight additional cases of hemangioblastomas diagnosed in elderly patients (out of 26 in subjects over age 18). Seven of the eight cases were sporadic, and one case was suspicious for being associated with the von Hippel-Lindau (VHL) syndrome. All eight cases had presented with symptoms related to compression, and surgical resection resulted in good clinical outcomes. Combined with our previous report, 14/103 (13.6%) of the hemangioblastomas diagnosed in a 15-year period in a single hospital were present in elderly patients, suggesting that the prevalence in elderly patients of hemangioblastomas is higher than previously expected.

Sporadic progressive ataxia and palatal tremor is a rare syndrome characterized by mid- to late-adult-onset symptomatic palatal tremor and slowly progressive cerebellar ataxia. To date, there has been only one autopsy report, which described a novel 4-repeat tauopathy with hypertrophic olivary degeneration and tau-positive inclusions in olivary neurons and dystrophic neuritic processes termed glomeruloid bodies. We report on 2 additional autopsy cases.Sections from selected paraffin-embedded brain regions were stained with hematoxylin and eosin/Luxol fast blue and processed for phosphorylated tau, 3-repeat tau, 4-repeat tau, neurofilament, glial fibrillary acid protein, phosphorylated α-synuclein, phosphorylated TAR DNA-binding protein 43, beta-amyloid, and p62 immunohistochemistry.Two male patients were aged 74 and 64 years at onset. Both had clinical findings consistent with progressive ataxia and palatal tremor and T2 hyperintensity in the bilateral olives on MRI. Pathological findings included bilateral hypertrophic olivary degeneration accompanied by glomeruloid bodies, 3-repeat and 4-repeat tau-positive neuronal inclusions in the olive, and additional tauopathy in the midbrain, pons, and thalamus. Cerebellar cortical degeneration was extensive, but involvement of the dentate was minimal. P62-positive, but tau- and TAR DNA-binding protein 43-negative, inclusions in the cerebellum of 1 case was also a feature.Whereas our findings are largely in keeping with the previously published case report, we found a more extensive and mixed 3/4-repeat tauopathy and additional cerebellar p62 pathology, highlighting our incomplete understanding of the pathogenesis of this disease. © 2017 International Parkinson and Movement Disorder Society.

Most cases of frontotemporal lobar degeneration (FTLD) are characterized by abnormal intracellular accumulation of either tau or TDP-43 protein. However, in ~10% of cases, composed of a heterogenous collection of uncommon disorders, the molecular basis remains to be uncertain. We recently discovered that the pathological changes in several tau/TDP-43-negative FTLD subtypes are immunoreactive (ir) for the fused in sarcoma (FUS) protein. In this study, we directly compared the pattern of FUS-ir pathology in cases of atypical FTLD-U (aFTLD-U, N = 10), neuronal intermediate filament inclusion disease (NIFID, N = 5) and basophilic inclusion body disease (BIBD, N = 8), to determine whether these are discrete entities or represent a pathological continuum. All cases had FUS-ir pathology in the cerebral neocortex, hippocampus and a similar wide range of subcortical regions. Although there was significant overlap, each group showed specific differences that distinguished them from the others. Cases of aFTLD-U consistently had less pathology in subcortical regions. In addition, the neuronal inclusions in aFTLD-U usually had a uniform, round shape, whereas NIFID and BIBD were characterized by a variety of inclusion morphologies. In all cases of aFTLD-U and NIFID, vermiform neuronal intranuclear inclusions (NII) were readily identified in the hippocampus and neocortex. In contrast, only two cases of BIBD had very rare NII in a single subcortical region. These findings support aFTLD-U, NIFID and BIBD as representing closely related, but distinct entities that share a common molecular pathogenesis. Although cases with overlapping pathology may exist, we recommend retaining the terms aFTLD-U, NIFID and BIBD for specific FTLD-FUS subtypes.

We report a case of de novo malignant ganglioglioma. A 61-year-old male presented with a 12-day history of headaches and general malaise. Pre-operative magnetic resonance imaging revealed an irregular enhancing mass in the left temporal lobe with associated dural enhancement and subacute subdural hematoma. The findings at surgery were of a vascular tumor intimately involving the surrounding white matter, with central necrosis. Histological and immunohistochemical studies showed an anaplastic ganglioglioma with World Health Organization grade IV characteristics. Gangliogliomas of the central nervous system are rare and are typified by a pediatric predilection and indolent behavior. A review of the de novo anaplastic and malignant gangliogliomas is presented.

We describe the clinical phenotype of nine kindred with presenile Alzheimer's disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

Sporadic Alzheimer's disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors (for example virus infections). To test this hypothesis, we are examining human genes relevant to herpes simplex virus type 1 (HSV-1) infection via genetic association studies in AD case-control samples. Recently, we found that a variant in TAP2, a major target used by HSV-1 to evade immune surveillance, is associated with AD. The present work analyses another gene involved in the host cell response to HSV-1, EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2; coding for PKR); PKR mediates the virus-induced shut-off of translation, and levels of activated PKR are high in the brains of AD patients. An EIF2AK2 SNP (rs2254958) located in the 5'-UTR region within an exonic splicing enhancer was found to be associated with AD. More specifically: the C allele was more commonly found in the patients and, compared to non-CC genotypes, the CC homozygotes showed earlier (around 3.3 years) onset of AD, especially in the absence of the APOE4 allele. These results further support the hypothesis that variants of human genes participating in HSV-1 infection modulate the susceptibility and/or clinical manifestations of AD.

X-linked myopathy with excessive autophagy (XMEA) is a childhood-onset, slowly progressive myopathy leading to lost ambulation after age 50 years.1 It is caused by mutations of the VMA21 gene, which encodes the assembly chaperone of the V-ATPase proton pump that acidifies organelles. Autophagosomal alkalinization impairs autophagy completion, which drives autophagosome proliferation and apparent damage to skeletal muscle.2 All known XMEA mutations reduce but do not eliminate VMA21 expression. Some cause greater VMA21 reduction than in classic XMEA and lead to a severe course with congenital/neonatal onset, extreme muscle wasting, and ventilation dependence. However, even with these mutations, no overt extramuscular disease is present.2–5 Given the vital role of V-ATPases in all cells, absence of manifest disease outside muscle is surprising. Possibly, extramuscular pathology is actually present but subclinical. In fact, patients with congenital/neonatal onset do have increased liver function tests, suggesting latent hepatopathy.

The observation showing that Lewy type synucleinopathy (LTS), the pathological hallmark of Parkinson’s disease (PD), is found in the gut of almost all PD subjects led to a substantial amount of research to develop a diagnostic procedure in living patients based on endoscopically obtained gastrointestinal biopsies. However, the existing studies have provided conflicting results regarding the sensitivity and specificity of gastrointestinal biopsies for the detection of LTS. We therefore undertook a multi-center staining and blinded judging of a common set of slides from colonic biopsies to determine the optimal protocol for the detection of LTS. Four different immunohistochemical methods, developed in four separate expert laboratories, were evaluated for their sensitivity and specificity to detect enteric LTS. Test sets of formalin-fixed, paraffin-embedded sections from biopsies of 9 PD subjects and 3 controls were stained with the 4 methods and graded by 4 different observers. Four types of staining morphology (granular staining in the lamina propria, perivascular/vascular wall staining in the submucosa, lacy-granular pattern in the submucosa and epithelial cell nuclear staining) were variably observed in the slides stained by the 4 methods. Positive alpha-synuclein staining was observed by all 5 judges in most of the slides from control cases, regardless of the staining methods that were used. Moreover, none of the tested method or staining pattern had a specificity and sensitivity more than 80 % regarding to PD. Overall, our study suggest that the tested methods are not adequate for the prediction of PD using gastrointestinal biopsies. Future studies are warranted to test new immunostaining methods. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0305-8) contains supplementary material, which is available to authorized users.

Sporadic Alzheimer's disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors. Binding with the transporter associated with antigen processing (TAP) is thought to be the main way in which herpes simplex virus type 1 (HSV-1) evades immune surveillance. Several TAP gene polymorphisms were examined and a TAP2 SNP (rs241448) associated with AD found in two independent case-control samples, especially in carriers of the APOE4 allele. These findings are consistent with the hypothesis that human genetic variants facilitating the access of HSV-1 to the brain might result in susceptibility to AD.

This is a clinicopathologic study of a prospective, clinic-based cohort of patients with frontotemporal dementia (FTD)/Pick complex, who were followed to autopsy. A total of 60 patients with the clinical syndromes of the behavioural variant of FTD (FTD-bv) (n = 32), primary progressive aphasia (PPA) (n = 22), corticobasal degeneration syndrome (CBDS) (n = 4) and progressive supranuclear palsy (PSP) (n = 2) at onset, referred to a cognitive neurology clinic who had subsequent post-mortem examination were included. The most common histological variety was motor neurone disease type inclusion (MNDI) (n = 18), followed by corticobasal degeneration (CBD) (n = 12), then Pick's disease (n = 6), dementia lacking distinctive histology (DLDH) (n = 6) and PSP (n = 3). Others fulfilled the histological criteria for Alzheimer's disease combined with glial pathology (n = 6), Alzheimer's disease only (n = 4), Lewy body variant (n = 2), prion disease (n = 1), vascular dementia (n = 1) and undetermined (n = 1). The most common first syndrome among the MNDI and DLDH (tau negative) pathologies was FTD-bv, but subsequently progressive aphasia (PA), occasionally CBDS and semantic dementia also developed. Tau positive histologies of CBD, PSP and Pick bodies were most frequently associated with PPA onset or CBDS/PSP, but behavioural symptoms were also common. Age of onset was earlier in tau negative cases, but the duration of illness and gender distribution were about the same in all histological variants. Although the tau negative and positive histologies are predicted to some extent by the clinical onset, the extent of the overlap and the convergence of the syndromes in the course of the disease argue in favour of maintaining the clinical and pathological varieties under a single umbrella.

We describe the clinical phenotype and pathology of a new autosomal dominant late-onset familial form of Alzheimer's disease in four extensive kindred originated in a genetically isolated population. Twelve affected and 16 unaffected members of these kindred were examined clinically, and a brain post-mortem study was carried out in one case. The preliminary genetic assessment included complex segregation analysis, evaluation of the power to detect linkage, and exclusion of candidate genes. Dementia has been recorded for six generations in ancestors of examined cases. Review of death certificates allowed linking of all subjects in four extensive pedigrees. Affected individuals examined had progressive memory loss with onset between 57 and 74 years of age, along with seizures, myoclonus and parkinsonism in advanced stages. The brain of the case examined post-mortem showed widespread neocortical neuritic plaques and neurofibrillary tangles (stage VI of Braak), amyloid angiopathy, and Lewy bodies restricted to limbic areas. Sequencing exons 16 and 17 of amyloid precursor protein, and exons 4-12 of presenilin 1 and presenilin 2 genes did not disclose any mutations. Genotyping with markers D21S265, D14S71, D14S77, D1S2850 and D1S479 located 1-3 cM from the previously reported genes further excluded linkage to these genes. Seven out of 12 cases were apolipoprotein E (APOE) epsilon3/3, although the presence of an APOE epsilon4 allele was associated with an increased risk of dementia (odd ratio 6.17; 95% confidence interval: 1.15-33.15), but not to an earlier age of onset. Complex segregation analysis showed that the best model fitting the data was that of a major gene (dominant) with a gene frequency close to 3% in this population. Simulation analysis predicted an average logarithm of odds (LOD) of 2.2 at = 0.05. These four families, which seem to be part of a common extended pedigree originated by a founder arriving in this region in the 18th century, represent an autosomal dominant late-onset familial Alzheimer's disease not linked to previously known genetic loci. The simulation analysis suggests that it will be feasible to locate a novel responsible gene in these kindred.

This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies.The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life.The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies.The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.

A referred cohort of 67 clinically defined PPA patients were compared to 99 AD patients with formal language and nonverbal cognitive tests in a case control design. Language fluency was determined at the first and last follow up visits. Quantitation of sulcal and ventricular atrophy on MRI was carried out in 46 PPA and 53 AD patients. Most PPA patients (57%) are relatively fluent when first examined. Visuospatial and memory functions are initially preserved. Aphemic, stuttering, “pure motor” presentation, or agrammatic aphasia are seen less frequently. Later most PPAs become logopenic and nonfluent, even those with semantic aphasia (dementia). In contrast, AD patients were more fluent and had relatively lower comprehension, but better overall language performance. MRI showed significant left sided atrophy in most PPA patients. Subsequent to PPA, 25 patients developed behavioral manifestations of frontotemporal dementia and 15 the corticobasal degeneration syndrome, indicating the substantial clinical overlap of these conditions. Language testing, particularly fluency scores supported by neuroimaging are helpful differentiating PPA from AD. The fluent–nonfluent dichotomy in PPA is mostly stage related. The aphemic-logopenic-agrammatic and semantic distinction is useful, but the outcomes converge. (JINS, 2003, 9, 710–719.)

Ten autopsied patients from a prospectively followed, clinically defined, neuropsychologically and radiologically documented cohort with primary progressive aphasia were histologically characterized. All were variants of frontotemporal degeneration (Pick complex): Pick body dementia, n =3, corticobasals degeneration (CBD), n =4, and tau and synuclein negative ubiquitinated inclusions of the motor neuron disease type, n =3. All shared superficial cortical spongiosis, neuronal loss, and gliosis. Although most patients had fluent anomic aphasia at onset, all progressed to a nonfluent or mute state. Comprehension, episodic memory, and activities of daily living were initially preserved. Three cases with Pick body dementia had verbal apraxia and stuttering at onset. Two of the patients with CBD pathology were older than the average primary progressive aphasia (PPA). All patients developed secondary syndromes either of frontotemporal dementia (FTD) and/or extrapyramidal-apraxic manifestations (CBD). By the time autopsy was obtained, the pathology appeared outside the language areas. Progressive aphasias secondary to Alzheimer's disease (AD) were excluded on the basis of early loss of memory and comprehension. Rather than the previously emphasized histological heterogeneity, clinically probable PPA has a predictive value of a group of related pathologies, collectively named frontotemporal degeneration, or Pick complex. This series of autopsied cases provides evidence for the clinical and pathological overlap of PPA with FTD and CBD, and contributes to the diagnostic and neuropsychological definition of PPA.

A 61-year-old man developed progressive ascending sensory loss to T8 and paraparesis over 4 weeks. MRI revealed ovoid T2-hyperintense lesions in juxtacortical and periventricular areas, and in the T7-T10 spinal segment, with varying degrees of peripheral gadolinium enhancement (figure 1). He received 5 days of high-dose corticosteroids and plasmapheresis for presumed demyelination, without clinical response. Brain biopsy showed vasculitis involving small arteries with transmural inflammatory cell infiltrates including numerous eosinophils (figure 2). Eosinophilic vasculitis can cause ischemic strokes1; it rarely involves the spinal cord.2 Our case illustrates that it should be considered in the differential diagnosis of CNS demyelination.

Chordoid meningioma (CM) is a rare subtype of meningioma, classified as grade II, which exhibits a high rate of recurrence following subtotal resection. We retrospectively examined nine cases of chordoid meningioma over a case series of 1743 meningiomas (0.52%) operated upon at our institution from 1995 to 2013. All the reported clinicopathological findings were analyzed. Two hundred and twenty-one CM cases have been published to date worldwide and few single-center large case series have been issued. Seventy-five percent of the cases that underwent subtotal resection at our institution had recurrence within 1 year. Total resection of the tumor should be the major objective of surgery to reduce the possibility of tumor recurrence. The percentage of chordoid features within the tumor specimen could assist in predicting the pathogenesis of the lesion. The correlation of the index of proliferation to recurrence rate is still controversial. Much debate exists with regard to the role of adjuvant radiotherapy in CM cases. Immunohistochemical, cytological and ultrastructural studies should be used in combination to assure a correct diagnosis of CM. Owing to the rare occurrence of this meningioma subtype, larger case series are required to assist in providing a reference for diagnosis and to improve the therapeutic management of CM.

Objective: To provide evidence for the hypothesis that the corticobasal degeneration syndrome (CBDs) overlaps significantly with primary progressive aphasia and frontotemporal dementia, and that CBDs is part of the Pick complex. Background: Corticobasal degeneration has been mainly described as a movement disorder, but cognitive impairment is also increasingly noted. Methods: Thirty-five cases of clinically diagnosed CBDs were followed-up with clinical, neuropsychological, and neuroimaging investigations. Twenty-nine patients were seen prospectively in movement disorder and cognitive neurology clinics; five of these came to autopsy. Six other autopsied cases that fulfilled the clinical criteria of CBDs were added with retrospective review of records. Results: All 15 patients presenting with movement disorders developed behavioral, cognitive, or language deficits shortly after onset or after several years. Patients presenting with cognitive problems (n = 20), progressive aphasia (n = 13), or frontotemporal dementia (n = 7) developed the movement disorder subsequently. Eleven cases with autopsy had CBD or other forms of the Pick complex. Conclusions: There is a clinical overlap between CBD, frontotemporal dementia, and primary progressive aphasia. There is also a pathologic overlap between these clinical syndromes. The recognition of this overlap will facilitate the diagnosis and avoid consideration of CBD as “heterogenous.”

A longitudinal study of the relationship between education and age of onset, rate of progression and cerebral lesion burden in a series of autopsy-confirmed demented patients with clinical and 6-monthly psychometric follow-up and autopsy was carried out. The study was conducted at the London Health Sciences Centre University Campus of the University of Western Ontario on 87 patients with pathologically confirmed Alzheimer's disease (60), dementia with Lewy bodies (11) or dementia with Lewy bodies plus Alzheimer's disease (16). Their educational attainment was classified as below high school, high school or above high school, and was similar to that of the age-adjusted general Ontario population. The age of onset of dementia, age at death, progression of cognitive decline, amount of neurodegenerative changes (senile plaques, neurofibrillary tangles and Lewy bodies) and cerebrovascular lesions (infarcts, lacunar state and white matter rarefaction) were assessed. Less educated patients became demented later and died later, but cognitive function declined at the same rate in all educational groups and there was no difference in the burden of neurodegenerative lesions between them. However, the less educated patients had more cerebrovascular lesions. It can be concluded that higher education does not modify the course of Alzheimer's disease, but lower education relates to the occurrence of cerebral infarcts. Our results suggest that a 'brain battering' model related to the higher prevalence of small vascular lesions in less educated individuals may explain their increased risk of dementia described by epidemiological studies better than the prevalent 'brain reserve' hypothesis.

Recent studies have indicated that, in the monkey, the rhinal cortex (consisting of the entorhinal and perirhinal cortices) is more important to visual recognition memory than the hippocampus or amygdala. The present study investigated the role of the entorhinal cortex in humans using memory scores from surgical epilepsy patients classified according to their mesial temporal lobe pathology. The temporal lobe removals included 4–5 cm of neocortex, amygdala, rhinal cortex and 2–3 cm of the hippocampus and parahippocampal gyrus. Compared to autopsied control subjects, all of the patients showed significant gliosis in the amygdala, but they differed as to whether or not there were entorhinal and\or hippocampal abnormalities. Both preoperatively and one or more years postoperatively, the patients performed tests of verbal recall (Wechsler Memory Scale Logical Memory), visual recall (Rey Figure), verbal recognition and visual recognition (Warrington Recognition Memory Test: Words and Faces, respectively). Preoperatively, patients with hippocampal pathology showed deficits in visual recall. Postoperatively, a significant drop in verbal and visual recall was seen only for patients who lost intact hippocampal tissue, irrespective of the condition of the excised entorhinal cortex. Together, the results argue that the hippocampus is more important than the entorhinal cortex for the recall of newly learned information.

OBJECTIVES To assess the role of cerebrovascular disease, sex, education, occupation, year of birth, leukoaraiosis, congophilic angiopathy, family history, and other demographic factors on the reported age of onset and rate of progression of Alzheimer’s disease. METHODS Analysis of data from the University of Western Ontario Dementia Study, a prospective longitudinal study of dementia patients with clinical and 6 monthly psychometric follow up to postmortem based in a university memory disorders clinic with secondary and tertiary referrals. There were 172 patients with dementia. The main outcome measures were the reported age of onset of cognitive decline as described by the family (available in 168) and rate of progression as measured during the linear phase of the extended scale for dementia, which could be calculated in 66. The cases subdivided into 49 cases of definite Alzheimer’s disease without infarcts, 25 cases of otherwise definite Alzheimer’s disease with infarcts, 79 cases of probable Alzheimer’s disease without infarcts, and 19 such cases with infarcts. RESULTS The age of onset was not influenced by the rate of progression, the presence of cerebral infarcts, or congophilic angiopathy. Educational level, occupational level, sex, family history, year of birth, reported age of onset, severity at entry, an ischaemic score, and the presence of leukoariosis, affected neither age of onset nor the rate of progression. An earlier year of birth had a major effect and higher education had a minor effect on earlier age of onset. The earlier the year of birth, the lower the educational level and the greater the accrual of cerebral infarcts. CONCLUSIONS Contrary to series without pathological verification, age of onset in this study was not affected by occupation. Education had a modest effect on earlier reported onset, probably reflecting earlier recognition. As birth year has a strong effect on educational level and the occurrence of cerebral infarcts, this must be taken into account when analysing for risk factors for Alzheimer’s disease.

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.

Capillary hemangiomas are benign vascular neoplasms rarely involving the spinal cord, where their usual location is extramedullary. A 59-year-old man presented with a 7-month history of progressive numbness which began in the left lower extremity and progressed across the lower back, right flank, trunk and into the right lower extremity with associated pressure and pain in his lower back. On magnetic resonance imaging, there was an avidly-enhancing thoracic intradural lesion that contained an extramedullary intradural component posteriorly, with an apparent intramedullary component anteriorly. Laminectomy of T7 - 8 was performed, and intradural exploration revealed a highly vascular-appearing tumor below the arachnoid, which was not completely dissected because it was densely adherent to the spinal cord. The pathological diagnosis was lobular capillary hemangioma with extra- and intramedullary components. We suggest this lesion should be considered in the differential diagnosis of spinal cord tumors with an intramedullary component.

Two previously distinct leukodystrophies, pigmentary orthochromatic leukodystrophy and hereditary diffuse leukoencephalopathy with spheroids, have recently been interpreted as variants of the same disease, adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP). We report a sporadic case of a 56-year-old male with ALSP presenting as frontotemporal dementia behavioral variant (FTD-bv). He had a history of depression and developed socially inappropriate behaviors consistent with FTD-bv. His first neurological exam was normal, but he developed new symptoms in the next 1.5 years: executive functional difficulties, anosognosia, urinary incontinence, epilepsy, extrapyramidal syndrome, severe gait disturbance, dysarthria, dysphagia and mutism. He died of pneumonia 20 months after initial presentation. MRI revealed increased T2-FLAIR signal in periventricular white matter and corpus callosum atrophy. Histology showed extensive demyelination of the centrum semiovale, most severe in frontal and temporal lobes, sparing U-fibers. There was no cortical neuronal loss, but selective loss of thalamic neurons. Histopathological hallmarks were cortical neuronal ballooning, white matter orthochromasia, pigmented macrophages, oligodendroglial loss, and axonal spheroids, some myelinated and some vacuolated. Morphometric studies for myelin, spheroids, oligodendrocytes and astrocytes showed that: 1) spheroids were most abundant in areas of partial demyelination rather than areas of extensive demyelination, being absent in normal appearing areas, 2) oligodendrocyte loss only occurred in regions of extensive demyelination and not in partial demyelination, and 3) there was no statistically significant change in number of astrocytes. There were also many more spheroids than physiologically expected in the gracile and cuneate nuclei. These findings suggest that the formation of spheroids is an early-stage event in disease progression. *These authors contributed equally to this work.